2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺类化合物的合成及抗流感活性研究  

Synthesis and anti-influenza activity of 2-[(7-trifluoro methylquinoline-4-yl)amino]benzamide derivatives

作　　者：焦思蒙 潘骏廷 张超[1] 张德良 刘晓平[1] 胡春[1] JIAO Si-meng;PAN Jun-ting;ZHANG Chao;ZHANG De-liang;LIU Xiao-ping;HU Chun(Key Laboratory of Structure-based Drug Design and Discovery(Shenyang Pharmaceutical University),Ministry of Education,Shenyang 110016,China)

机构地区：[1]沈阳药科大学基于靶点的药物设计与研究教育部重点实验室,辽宁沈阳110016

出　　处：《中国药物化学杂志》2022年第4期259-265,334,共8页Chinese Journal of Medicinal Chemistry

基　　金：国家自然科学基金项目(21342006)。

摘　　要：目的设计合成一系列2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺类化合物,以期得到抗流感活性较好的新化合物。方法以3-三氟甲基苯胺和乙氧基亚甲基丙二酸二乙酯为起始原料,经取代、环合、水解、脱羧、氯代、取代和水解反应得到关键中间体2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酸(9),9和胺类化合物经缩合反应得到2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺类化合物。采用酶联免疫分析法,测试了8个目标化合物和中间体8的细胞毒性及抗流感病毒活性。结果设计并合成了8个未见文献报道的2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺类化合物,其结构均经质谱和核磁共振氢谱确证。细胞毒性测试和细胞病变保护实验结果显示,大部分目标化合物细胞毒性较低,并能不同程度地提高MDCK细胞被流感病毒感染后的存活能力,其中化合物10h活性最强。结论2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺类化合物细胞毒性较小且较为显著地提高了MDCK细胞被流感病毒感染后的存活能力,具有进一步的研究价值。As known,RNA polymerase as a highly conservative protein plays an important role in the replication,transcription and translation of influenza viruses,and is a prominently biological target in discovery of novel drug for treatment of influenza.In order to discover the novel anti-influenza agents,a new series of 2-[(7-trifluoromethylquinolin-4-yl)amino]benzamides as target compounds(10a-10h)were designed with antrafenine as the lead compound and synthesized through a series of reactions from 3-trifluoromethylaniline and diethyl ethoxymethylene malonate as the raw materials,and their structures were characterized by HR-MS and1H-NMR.The cytotoxicity and anti-influenza activity of the target compounds were examined by enzyme linked immunosorbent assay.The results of cytotoxicity assay and cytopathic effect assay have shown that most of the target compounds have low cytotoxicity and can improve the considerable protective activity of M DCK cells infected by influenza virus.The target compound 10h has the strongest anti-influenza virus activity,which will result in a discovery of a novel antiviral candidate drug based on the future research.

关 键 词：喹啉类化合物 苯甲酰胺类化合物 RNA聚合酶 抗流感药物 合成 

分 类 号：R914[医药卫生—药物化学]